Perindopril

ABSTRACT

A pharmaceutically acceptable salt of perindopril of formula (I) is made from a protected precursor compound of formula (II) wherein R represents a carboxyl protecting group, which process comprises subjecting a compound of formula (II) to deprotection of the carboxylic group COOR attached to the heterocyclic ring so as to yield the corresponding free acid, which deprotection is carried out in the presence of a base which forms a pharmaceutically acceptable salt with the free acid formed by the deprotection

This application is a 35 U.S.C. §371 U.S. National Stage Application ofInternational Application No. PCT/GB2003/004981, filed on Nov. 18, 2003,claiming the priority of Great Britain Application No. 0226885.2, filedNov. 18, 2002, the entire disclosures of which are incorporated hereinby reference in their entireties.

This invention relates to a process for preparing a pharmaceuticallyacceptable salt of perindopril, and a novel polymorphic form thereof.

Perindopril is the international non-proprietary name of(2S,3aS,7aS)-1-{2-[1-(ethoxycarbonyl)-(S)-butylamino]-(S)-propionyl}-octahydroindole-2-carboxylicacid. Perindopril is known to have therapeutic application as anangiotensin—converting enzyme (ACE) inhibitor. ACE is a peptidyldipeptidase which catalyzes the conversion of angiotensin I toangiotensin II, as well as causing the degradation of bradykinin.Angiotensin II is a vasoconstrictor which also stimulates aldosteronesecretion by the adrenal cortex. Inhibition of ACE has, therefore, beenshown to have therapeutic utility in patients suffering from diseasestates such as hypertension and congestive heart failure. In addition,it has been discovered that ACE inhibitors are useful in treatingcognitive disorders.

Perindopril has the following structural formula (I)

Perindopril is described in U.S. Pat. No. 4,508,729. Preparativeprocesses described in this U.S. patent are carried out in an alcoholicmedium, and in the presence of a neutral dehydrating agent and anorganic or inorganic cyanoborohydride. Deprotection processes can becarried out where necessary, for example with reference to hydrolysisand/or hydrogenolysis.

U.S. Pat. No. 4,914,214 describes a process for the preparation ofperindopril and its t-butylamine salt. The process comprisescondensation of a protected ester of(2S,3aS,7aS)-2-carboxyperhydroindole with the (S,S) diastereoisomer ofN-[(S)-1-carbethoxybutyl]-(S)-alanine, followed by deprotectionemploying charcoal containing 5% palladium and water.Tertiary-butylamine is then added to yield the t-butylamine salt ofperindopril.

PCT patent application WO 01/87835 describes a novel crystalline form,namely α crystalline form, of the t-butylamine salt of perindopril,processes of preparing the same and pharmaceutical formulationscontaining the same.

PCT patent application WO 01/87836 describes a novel crystalline form,namely ∃ crystalline form, of the t-butylamine salt of perindopril,processes of preparing the same and pharmaceutical formulationscontaining the same.

PCT patent application WO 01/87835 describes a novel crystalline form,namely γ crystalline form, of the t-butylamine salt of perindopril,processes of preparing the same and pharmaceutical formulationscontaining the same.

PCT patent application WO 01/58868 describes a process of preparingperindopril or pharmaceutically acceptable salts thereof, which processprovides perindopril, or a salt thereof, with improved purity. Moreparticularly, the level of known impurities associated with perindoprilor a salt thereof, prepared according to PCT patent application WO01/58868, is described as being less than 0.2 or 0.1% by weight.Intermediate process steps are carried out in the presence of1-hydroxybenzotriazole, dicyclohexylcarbodiimide and optionallytriethylamine, and at a temperature in the range of 20 to 77 EC,followed by deprotection and where required salt conversion.

Prior art processes for the preparation of perindopril, orpharmaceutically acceptable salts thereof, have generally tended to betime-consuming and have often resulted in undesirable associatedimpurities, such as diketopiperazine analogues. There is, therefore, aneed for an improved process for preparing perindopril, orpharmaceutically acceptable salts thereof, which alleviates the abovementioned problems.

We have now developed a process for preparing a pharmaceuticallyacceptable salt of perindopril, which is advantageous in terms of afaster reaction time compared to known processes for the preparation ofa pharmaceutically acceptable salt of perindopril, and also in obviatingthe production of undesirable impurities so as to achieve a highly pureproduct.

In accordance with one aspect of the present invention, there isprovided a process for preparing a pharmaceutically acceptable salt ofperindopril of formula (I) from a protected precursor compound offormula (II)

wherein R represents a carboxyl protecting group, which processcomprises subjecting a compound of formula (II) to deprotection of thecarboxylic group COOR attached to the heterocyclic ring so as to yieldthe corresponding free acid, which deprotection is carried out in thepresence of a base which forms a pharmaceutically acceptable salt withsaid free acid formed by said deprotection.

Typically, R can represent any suitable carboxyl protecting group thatcan be selectively removed by a process according to the presentinvention. Preferably, R can represent optionally substituted aralkyl,especially optionally substituted benzyl. R can, therefore, typicallyrepresent unsubstituted benzyl; alternatively substituted benzyl can beemployed, such as 4-halo substituted, or 4-C₁₋₄alkoxy substitutedbenzyl, especially 4-C1benzyl, or 4-methoxy benzyl.

Suitably, deprotection as employed in a process according to the presentinvention can comprise hydrogenolysis in the presence of a noble metalcatalyst, preferably palladium-on-chacoal.

The process of the present invention is advantageous in achieving ahighly pure product. A pharmaceutically acceptable salt of perindoprilprepared by a process according to the present invention is preferablymore than about 99% w/w pure, and more preferably more than about 99.5%w/w pure. The purity of a pharmaceutically acceptable salt ofperindopril prepared by a process according to the present invention canbe further enhanced by an optional crystallisation step in a suitablesolvent, such as ethyl acetate, isopropanol or the like, so as to obtaina pharmaceutically acceptable salt of perindopril which is preferablyabout 99.8% w/w pure.

Preferably, the base employed in the process of the present invention isselected so as to form a pharmaceutically acceptable salt with the freeacid formed by the deprotection as indicated above, whereby it ispossible to obtain a pharmaceutically acceptable salt of perindoprildirectly from such a reaction work-up. In a particularly preferredembodiment according to the present invention the base comprisest-butylamine and as such a preferred process according to the presentinvention can provide a highly pure t-butylamine salt of perindoprildirectly from the reaction process.

According to the above preferred embodiment of the present invention,there is provided a process for preparing perindopril t-butylamine(which is well known to those of skill in the art as being perindoprilerbumine) from a protected precursor compound of formula (II)substantially as hereinbefore described (preferably a benzyl protectedprecursor compound of formula (II) where R represents benzyl), whichprocess comprises subjecting a compound of formula (II) to deprotection(preferably hydrogenolysis in the presence of a noble metal catalystsuch as palladium-on-chacoal) of the carboxylic group COOR attached tothe heterocyclic ring so as to yield the corresponding free acid, whichdeprotection is carried out in the presence of t-butylamine so as toform the t-butylamine salt of perindopril.

Suitably a precursor compound of formula (II) is initially dissolved inan alkanol solvent, such as isopropanol or the like, followed byaddition of the base thereto. This is further followed by thedeprotection of the carboxylic group COOR, suitably by the addition ofpalladium-on-charcoal and hydrogenation for several hours. The alkanolsolvent is suitably concentrated under vacuum and replaced by a waterimmiscible solvent, such as ethyl acetate or the like. The resultingsolids can then be cooled and filtered to yield a pharmaceuticallyacceptable salt of perindopril.

The process according to the present invention substantially ashereinbefore described may further comprises hydrating apharmaceutically acceptable salt of perindopril obtained by the processso as to yield a pharmaceutically acceptable salt of hydratedperindopril of formula (Ia)

wherein n is an integer of 1 to 5, or a reciprocal of integers 2 to 5.Hydration can be by way of the addition of water or by drying in air.

Preferably n is 1, whereby a pharmaceutically acceptable salt ofperindopril monohydrate is formed by a process according to the presentinvention.

The present invention also provides a process for preparing amonohydrate of a pharmaceutically acceptable salt of perindopril, whichprocess comprises hydrating a pharmaceutically acceptable salt ofperindopril so as to yield said monohydrate. Hydration can be by way ofthe addition of water or by drying in air, and preferably perindoprilt-butylamine is hydrated to yield perindopril t-butylamine monohydrate.

The present invention further provides a pharmaceutically acceptablesalt of perindopril optionally in hydrated form, prepared by a processsubstantially as hereinbefore described. In particular, apharmaceutically acceptable salt of hydrated perindopril of formula (Ia)is provided

wherein n is an integer of 1 to 5, or a reciprocal of integers 2 to 5.Preferably, n is 1. A preferred pharmaceutically acceptable salt ofhydrated perindopril of formula (Ia) is the t-butylamine salt. In aparticularly preferred embodiment, the present invention providesperindopril t-butylamine (or erbumine) monohydrate.

The present invention also provides perindopril t-butylamine monohydratehaving an X-ray diffractogram, or substantially the same X-raydiffractogram, as set out in FIG. 1. More particularly, perindoprilt-butylamine monohydrate according to the present invention can becharacterised as having an X-ray powder diffraction pattern withcharacteristic peaks (2θ): 9.5504, 14.8600, 15.7486, 16.5400, 20.0400,21.0499, 22.0600, 24.1744, 26.3300 and 27.1600.

Further characterising data for perindopril t-butylamine monohydrateaccording to the present invention as obtained by X-ray diffraction isshown in following Table 1.

TABLE 1 2θ d FWHM Intensity Integrated Peak No. (deg) (A) I/Il (deg)(Counts) I (Counts) 1 8.6400 10.22611 10 0.57600 151 6899 2 9.55049.25324 73 0.50470 1090 28204 3 10.5940 8.34394 5 0.97200 79 4071 413.6000 6.50569 6 0.42860 91 2112 5 14.1400 6.25844 14 0.47120 215 52106 14.8600 5.95678 22 0.59000 332 10293 7 15.7486 5.62262 75 0.14270 111149244 8 16.5400 5.35533 30 0.72500 450 15749 9 17.5400 5.05220 160.67120 231 9128 10 18.6100 4.76406 17 0.56000 249 7981 11 20.04004.42722 31 0.51660 458 13471 12 21.0499 4.21704 100 0.90700 1488 6386013 22.0600 4.02618 50 0.59480 747 23998 14 23.1600 3.83738 17 0.71720253 12014 15 24.1744 3.67860 47 0.50030 705 17912 16 24.8000 3.58721 50.26000 73 1463 17 26.3300 3.38213 31 0.94000 468 19402 18 27.16003.28062 20 0.68500 292 9230 19 28.4444 3.13534 15 0.96890 223 11023 2030.8000 2.90071 7 0.59340 99 3196 21 31.8000 2.81173 9 0.65600 130 435622 32.5600 2.74782 11 0.61340 163 4411 23 33.2400 2.69314 6 0.75000 953116 24 34.1800 2.62120 4 0.64000 61 2155 25 35.4728 2.52857 7 0.85430104 4353 26 36.8838 2.43502 6 0.61900 93 2985 27 38.7340 2.32285 40.50800 55 1432

Perindopril as provided by the present invention has therapeutic utilityas an ACE inhibitor.

In addition, the present invention further provides a method ofinhibiting ACE in a patient in need thereof comprising administering tosaid patient an effective ACE inhibitory amount of perindopril(preferably perindopril t-butylamine monohydrate) as provided accordingto the present invention.

The present invention also provides use of perindopril as providedaccording to the present invention (preferably perindopril t-butylaminemonohydrate) in the manufacture of a medicament for inhibiting ACE.

A patient can be in need of treatment to inhibit ACE, for example whenthe patient is suffering from hypertension, chronic congestive heartfailure, or the like. Inhibition of ACE reduces levels of angiotensin IIand thus inhibits the vasopressor, hypertensive and hyperaldosteronemiceffects caused thereby. Inhibition of ACE would also potentiateendogenous levels of bradykinin. An effective ACE inhibitory amount ofperindopril as provided according to the present invention is thatamount which is effective in inhibiting ACE in a patient in need thereofwhich results, for example, in a hypotensive effect.

In effecting treatment of a patient, perindopril as provided accordingto the present invention can be administered in any form or mode whichmakes the compound bioavailable in effective amounts, including oral andparenteral routes. For example, perindopril as provided according to thepresent invention can be administered orally, subcutaneously,intramuscularly, intravenously, transdermally, intranasally, rectally,and the like. Oral administration is generally preferred. One skilled inthe art of preparing formulations can readily select the proper form andmode of administration depending upon the disease state to be treatedand the stage of the disease.

Perindopril as provided according to the present invention can beadministered in the form of pharmaceutical compositions or medicamentswhich are prepared by combining the perindopril according to the presentinvention with pharmaceutically acceptable carriers, diluents orexcipients therefor, the proportion and nature of which are determinedby the chosen route of administration, and standard pharmaceuticalpractice.

In another embodiment, the present invention provides pharmaceuticalcompositions comprising an effective ACE inhibitory amount ofperindopril as provided according to the present invention (preferablyperindopril t-butylamine monohydrate), together with one or morepharmaceutically acceptable carriers, diluents or excipients therefor.

By “pharmaceutically acceptable” it is meant that the carrier, diluentor excipient must be compatible with perindopril as provided accordingto the present invention, and not be deleterious to a recipient thereof.

The pharmaceutical compositions or medicaments are prepared in a mannerwell known in the pharmaceutical art. The carrier, diluent or excipientmay be a solid, semi-solid, or liquid material, which can serve as avehicle or medium for the active ingredient. Suitable carriers, diluentsor excipients are well known in the art. Pharmaceutical compositionsaccording to the present invention may be adapted for oral or parenteraluse and may be administered to the patient in the form of tablets,capsules, suppositories, solutions, suspensions or the like.

The pharmaceutical compositions may be administered orally, for example,with an inert diluent or with an edible carrier. They may be enclosed ingelatin capsules or compressed into tablets. For the purpose of oraltherapeutic administration, a monohydrate according to the presentinvention may be incorporated with excipients and used in the form oftablets, capsules, elixirs, suspensions, syrups and the like.

The tablets, pills, capsules, and the like may also contain one or moreof the following adjuvants: binders, such as microcrystalline cellulose,gum tragacanth or gelatin; excipients, such as starch or lactose;disintegrating agents such as alginic acid, corn starch and the like;lubricants, such as magnesium stearate; glidants, such as colloidalsilicon dioxide; and sweetening agents, such as sucrose or saccharin.When the dosage unit form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier such as polyethyleneglycol or a fatty oil. Other dosage unit forms may contain other variousmaterials which modify the physical form of the dosage unit, forexample, as coatings. Thus, tablets or pills may be coated with sugar,shellac, or other enteric coating agents. A syrup may contain, inaddition to the active ingredient, sucrose as a sweetening agent andcertain preservatives. Materials used in preparing these variouscompositions should be pharmaceutically pure and non-toxic in theamounts used.

For the purpose of parenteral administration perindopril as providedaccording to the present invention may be incorporated into a solutionor suspension. The solutions or suspensions may also include one or moreof the following adjuvants: sterile diluents such as water forinjection, saline solution, fixed oils, polyethylene glycols, glycerine,propylene glycol or other synthetic solvents; antibacterial agents suchas benzyl alcohol or methyl paraben; antioxidants such as ascorbic acidor sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; and buffers such as acetates, citrates orphosphates. The parenteral preparation can be enclosed in ampoules,disposable syringes or multiple dose vials made of glass or plastic.

The present invention will now be further illustrated by the followingFIGURE and Examples, which do not limit the scope of the invention inany way.

FIG. 1: X-ray diffraction pattern of perindopril erbumine monohydrateaccording to the present invention. The sample was analysed using aShimadzu-6000 x-ray diffractometer. The source used was K_(α)monochromatic radiation of Cu having wavelength of 1.5406 A°. TheDivergent Slit used was 1°. The Receiving Slit was 0.30 mm. TheScintillation counter was used as the detector, with the range beingfrom 3° to 40° (2θ) with a scan speed of 2° per minute.

EXAMPLE 1

The benzyl ester of(2S,3aS,7aS)-1-{2-[1-(ethoxycarbonyl)-(S)-butylamino]-(S)-propionyl}-octahydroindole-2-carboxylicacid, namely benzyl perindopril, (10 gms) was dissolved in isopropanol(100 ml). To the clear solution, t-butylamine (2.5 gms) and 10% w/wpalladium on charcoal (2 gms) was added. The reaction mixture washydrogenated at a pressure of 1 kg/cm² for 2 hours.

The reaction mass was filtered to remove the catalyst. The solvent wasconcentrated under vacuum and isopropanol was replaced by simultaneousaddition of ethyl acetate. The solids obtained were cooled to 0 EC andfiltered to obtain perindopril erbumine (7.8 gms).

EXAMPLE 2

Perindopril erbumine (10 gms) was suspended in acetone (80 ml). To thiswas added water (0.4 ml) and the contents heated to dissolve the solidsand cooled to ambient. The resulting slurry was filtered to obtainperindopril erbumine monohydrate (9.4 gms).

EXAMPLE 3

Perindopril erbumine (20 gms) was suspended in ethyl acetate (300 ml).To this was added water (1.5 ml) and the contents heated to dissolve thesolids and cooled to 10 EC. The resulting slurry was filtered to obtainperindopril erburnine monohydrate (17 gms).

EXAMPLE 4

Perindopril erbumine (5 gms) was suspended in acetonitrile (75 ml). Tothis was added water (0.4 ml) and the contents heated to dissolve thesolids and cooled to 0 EC. The resulting slurry was filtered to obtainperindopril erbumine monohydrate (2.9 gms).

EXAMPLE 5

Perindopril erbumine (20 gms) was suspended in ethyl acetate (300 ml).The contents were heated to dissolve the solids and cooled to 10 EC. Theresulting slurry was filtered and dried in air having a relativehumidity of at least 75% to give perindopril erbumine monohydrate (17gms).

EXAMPLE 6

Preparation of perindopril erbumine monohydrate Raw Materials:- 1.Perindopril erbumine anhydrous = 10 gm. 2. Isopropyl alcohol = 70 ml. 3.Water = 2 ml. 4. Ethyl acetate = 85 ml.Procedure:—

-   -   1. Charge 10 gm of perindopril erbumine (anhydrous) in round        bottom flask. Add 70 ml isopropyl alcohol. Stir for ½ hr.        (around 95% product dissolved).    -   2. Add 2 ml of water. Stir for 15 min (clear solution obtained).    -   3. Stir reaction mass at 38-40° C. for 2 hrs.    -   4. Distill out isopropyl alcohol completely under vacuum (below        600 mm) below 40° C. (Gel type material observed.)    -   5. Charge 30 ml ethyl acetate. Stir for 15 min below 40° C.        (clear solution observed). Distill under vacuum below 40° C.        (semi-solid observed).    -   6. Charge 40 ml ethyl acetate at 36-38° C. Stir for 15 min (free        solid observed).    -   7. Stir 1 hr at room temperature (25-30° C.). (Free crystalline        solid observed.)    -   8. Cool to 10° C. Stir for 2 hrs.    -   9. Filter solid and wash with 15 ml ethyl acetate. Suck dry for        2 hrs.    -   10. Dry under vacuum below 40° C. for 12 hrs.        Water Content=3.2-3.8%        M.P=145-150° C.

EXAMPLE 7

The following tablets were prepared:

(a) Formulation I:

Strengths Ingredients 2 mg 4 mg 8 mg Perindopril Erbumine 2 mg 4 mg 8 mgMonohydrate Maize starch 5 mg 10 mg 20 mg Lactose anhydrous 12.5 mg 25.0mg 100.0 mg Microcrystalline 25.10 mg 50.20 mg 100.40 mg celluloseMagnesium stearate 0.4 0.8 1.6 Total weight 45.0 mg 90.0 mg 180.0 mg

Procedure: Sift the above ingredients through respective sieves. Mix theingredients in a suitable blender. Compress the tablets in the suitabletoolings.

(b) Formulation II:

Strengths Ingredients 2 mg 4 mg 8 mg Perindopril Erbumine 2 mg 4 mg 8 mgMonohydrate Maize starch 10 mg 10 mg 10 mg Lactose anhydrous 25 mg 25.0mg 25.0 mg Microcrystalline 52.2 mg 49.20 mg 45.20 mg cellulose Yellowoxide of Iron — 1.0 — Red oxide of Iron — — 1.0 Hydrogenated castor 0.8mg 0.8 mg 0.8 mg oil Total weight 90.0 mg 90.0 mg 90.0 mgProcedure:

-   1) Dissolve Perindopril Erbumine Monohydrate in ethanol.-   2) Granulate the above ingredients except hydrogenated castor oil    with the above solution. Dry the granules and size.-   3) Lubricate with hydrogenated castor oil in suitable blender.    Compress the granules in the suitable tooling

1. A process for preparing a pharmaceutically acceptable salt ofperindopril of formula (I) from a protected precursor compound offormula (II)

wherein R represents a carboxyl protecting group, which processcomprises subjecting a compound of formula (II) to deprotection of thecarboxylic group COOR attached to the heterocyclic ring so as to yieldthe corresponding free acid, which deprotection is carried out in thepresence of a base which forms a pharmaceutically acceptable salt withsaid free acid formed by said deprotection.
 2. A process according toclaim 1, wherein R represents optionally substituted aralkyl.
 3. Aprocess according to claim 2, wherein R represents unsubstituted benzyl.4. A process according to claim 2, wherein R represents 4-halosubstituted, or 4-C₁₋₄ alkoxy substituted benzyl.
 5. A process accordingto claim 4, wherein R represents 4-C1benzyl, or 4-methoxy benzyl.
 6. Aprocess according to claim 1, wherein said deprotection compriseshydrogenolysis in the presence of a noble metal catalyst.
 7. A processaccording to claim 6, wherein the noble metal catalyst comprisespalladium-on-charcoal.
 8. A process according to claim 1, wherein saidbase comprises t-butylamine.
 9. A process for preparing perindoprilt-butylamine from a protected precursor compound of formula (II)

wherein R represents a carboxyl protecting group, which processcomprises subjecting a compound of formula (II) to deprotection of thecarboxylic group COOR attached to the heterocyclic ring so as to yieldthe corresponding free acid, which deprotection is carried out in thepresence of t-butylamine so as to form the t-butylamine salt ofperindopril.
 10. A process according to claim 9, wherein R representsunsubstituted benzyl.
 11. A process according to claim 9, whereindeprotection comprises hydrogenolysis in the presence ofpalladium-on-charcoal.
 12. A process according to claim 1, which furthercomprises hydrating a pharmaceutically acceptable salt of perindoprilobtained by said process so as to yield a pharmaceutically acceptablesalt of hydrated perindopril of formula (Ia)

wherein n is an integer of 1 to 5, or a reciprocal of integers 2 to 5.13. A process according to claim 12, wherein n is
 1. 14. A process forpreparing a monohydrate of a pharmaceutically acceptable salt ofperindopril, which process comprises hydrating a pharmaceuticallyacceptable salt of perindopril so as to yield said monohydrate.
 15. Aprocess according to claim 12, wherein perindopril t-butylamine ishydrated to yield perindopril-t-butylamine monohydrate.